Interleukin-6; pathogenesis and treatment of autoimmune inflammatory diseases

Transcription

1 54 Review Article Interleukin-6; pathogenesis and treatment of autoimmune inflammatory diseases Toshio Tanaka 1, 2), Masashi Narazaki 3), Kazuya Masuda 4) and Tadamitsu Kishimoto 4, ) 1) Department of Clinical Application of Biologics, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan 2) Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan 3) Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka University, Osaka, Japan 4) Laboratory of Immunoregulation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan Interleukin-6 (IL-6), originally identified as a B cell stimulatory factor-2, is a typical cytokine featuring redundancy and pleiotropic activity. A transient expression of IL-6 participates in host defense against acute environmental stress such as infections and injuries by activating immune responses, hematopoiesis and acute phase reactions. However, its abnormal, persistent production plays an important pathological role in the development of various autoimmune inflammatory diseases, so that it was hypothesized that IL-6 blockade would constitute a novel strategy for the treatment of such diseases and to this purpose tocilizumab, a humanized anti- IL-6 receptor monoclonal antibody, was developed. Clinical trials have indeed proved the efficacy and tolerable safety of tocilizumab for patients with moderate to severe rheumatoid arthritis, and it is now used as a made-in-japan innovative biologic for rheumatoid arthritis in more than 90 countries worldwide, as well as for patients with Castleman's disease and systemic and polyarticular juvenile idiopathic arthritis. Moreover, favorable results of recent clinical trials or case reports of off-label use with tocilizumab indicate that it is likely to be broadly applicable for the treatment of various autoimmune inflammatory diseases. Its wider application for various diseases as well as clarification of the mechanism(s) through which IL-6 blockade becomes clinically efficacious and of the etiology of dysregulated persistent IL-6 production in such diseases are important issues for future studies. Rec.11/1/2012, Acc.11/26/2012, pp54-65 Correspondence should be addressed to: Tadamitsu Kishimoto, Laboratory of Immunoregulation, WPI Immunology Frontier Research Center, Osaka University, 8F IFReC Building, 3-1 Yamada-oka, Suita City, Osaka , Japan. Phone: , Fax: , kishimoto@ifrec.osaka-u.ac.jp Key words anti-interleukin-6 receptor antibody, autoimmunity, inflammation, interleukin-6, tocilizumab

2 55 Fig.1 The human IL-6 structure Schematic representation of the human IL-6 structure shows the four long -helices, from A to D and three connecting loops. Two disulfide bonds are contained in loop A-B. Site I on the C-terminal end of helix D interacts with IL-6R, site II, located on helices A and C, interacts with one gp130, while site III on the N-terminal end of helix D interacts with another gp130. Fig.2 Pleiotropic activity of IL-6 IL-6 induces specific gene expression and cell differentiation. It induces production of acute phase proteins such as CRP, serum myloid A, fibrinogen, and hepcidin, whereas it reduces synthesis of albumin in hepatocytes. In bone marrow, IL-6 induces maturation of megakaryocytes into platelets. In addition, IL-6 induces Th17 differentiation from naïve CD4- positive T cells, whereas it inhibits Treg differentiation. It also induces cytotoxic T cell differentiation from CD8-positive T cells, and immunoglobulin synthesis in activated B cells. Moreover, IL-6 acts on synovial fibroblasts to produce RANKL and VEGF, which promote differentiation of osteoclasts and angiogenesis, respectively. Finally, IL-6 stimulates dermal fibroblasts to produce collagen. CRP: C-reactive protein, Treg: regulatory T cells, RANKL: receptor activator of NF- B ligand, VEGF: vascular endothelial growth factor Discovery of interleukin-6 Biological function of IL-6

3 56 ï Signaling system of IL-6 Fig.3 The IL-6 receptor system The figure on the left shows the IL-6 receptor system. After binding of IL-6 to the IL-6 receptor (IL-6R), the IL-6/IL-6R complex associates with gp130 and induces homodimerization of gp130, which triggers activation of JAKs and tyrosine-phosphorylation of cytoplasmic part of gp130. The phosphorylated gp130 then recruits STAT3 via the SH2- domain. Tyrosine-phosphorylated gp130 also recruits SHP-2 and activates the MAPK pathway. Next, activated STAT3 translocates into the nucleus and regulates transcription for various sets of genes including SOCS, which binds to JAK or gp130 and turns off IL-6 signals. The figure on the right shows that tocilizumab binds to transmembrane and soluble IL-6R and inhibits IL-6 binding to both types of IL-6R. JAKs: Janus kinase family tyrosine kinases, STAT3: signal transducer and activator of transcription 3, SHP-2: SH2-domain containing protein tyrosine phosphatase-2, MAPKs: mitogen-activated protein kinase, SOCS: suppressor of cytokine signaling

4 57 Fig.4 Transcriptional regulation of IL-6 gene IL-6 gene activation is positively or negatively regulated by transcriptional factors or micrornas. Several cisacting elements are shown. NF- B: nuclear factor kappa B, SP1: specificity protein 1, NF-IL6: nuclear factor IL-6, AP-1: activator protein 1, IRF-1: interferon regulatory factor 1, Tax: HTLV-1-derived transactivator protein, TAT: HIV-1 transactivator of the transcription, HBVX: hepatitis B virus X protein, GR: glucocorticoid receptor, ER: estrogen receptor, Rb: retinoblastoma, PPAR : peroxisome proliferator-activated receptor, Ahr: aryl hydrocarbon receptor, mir: microrna, IRAK1: interleukin-1 receptor-associated kinase 1, STAT3: signal transducer and activator of transcription 3, MRE: multiple response element Regulatory mechanism of IL-6 production

5 58 Fig.5 Posttranscriptional regulation of IL-6 mrna IL-6 expression is posttransciptionally regulated by several RNA binding proteins or micrornas. AU-rich elements (AREs) located in 3 untranslated region (UTR) of IL-6 mrna are shown. ORF: open reading frame, TTP: tristetraprolin, BRF-1: butyrate response factor-1, mir: microrna Fig.6 Arid5a counteracts the destabilizing effect of regnase-1 on IL-6 mrna Regnase-1 accerates IL-6 mrna degradation, whereas arid5a conteracts the destabilizing effect of regnase-1. The balance between arid5a and regnase- 1 plays an important role in IL-6 mrna stability. LPS: lipopolysaccharide, TLR4: Toll-like receptor 4, UTR: untranslated region

6 59 ï Pathogenesis of IL-6 in the development of autoimmune inflammatory diseases IL-6 targeting as strategy for autoimmune inflammatory diseases

7 60 Efficacy of tocilizumab for rheumatoid arthritis Efficacy of tocilizumab for systemic juvenile idiopathic arthritis

8 61 Efficacy of tocilizumab for Castleman s disease IL-6 targeting as strategy for various other autoimmune inflammatory diseases

9 62 Table 1 Ongoing clinical trials of tocilizumab for treatment of diseases other than rheumatoid arthritis and juvenile idiopathic arthritis, registered with ClinicalTrials.gov Current clinical trials of tocilizumab are listed. RA: rheumatoid arthritis, KSHV: Kaposi's sarcoma herpes virus, GVHD: graft-versus-host disease, SJIA: systemic juvenile idiopathic arthritis Conclusion and future prospects

10 63 Conflict of interest

11 64

12 65